For over a hundred years it has been empirically known that shape of cells within tissues and organs is an indicator of health or disease. The field of pathology is largely based on the premise the cell shape contributes to tissue morphology which can serve as a diagnostic of disease initiation and progression. Nevertheless, the biological basis for these empirical observations has never been tackled in a systematic manner. We have been studying how cell shape affects information flow through cell signaling networks. We use a combination of mathematical analyses, numerical simulations and live cell imaging to understand the role of cell shape in signal transduction. Our overall hypothesis is that cell shape can regulate dynamic membrane localization of upstream signaling components such as receptors and this localization coupled with network topology and scaffolding of select isoforms of negative regulators in the cytoplasm are major determinants of the spatial specificity of signaling. To test this hypothesis we will 1) study the role the of cell shape in the dynamics in the plane of the membrane of receptors that regulate the cAMP and MAP-kinase pathways 2) study the relationship between cell shape and different isoforms of cAMP phosphodiesterases in regulating receptor- stimulated cAMP levels and activated MAPK-1,2 within microdomains 3) study the role of how regulated scaffolding of the different isoforms of the negative regulators cAMP phosphodiesterases and phosphatases controls receptor triggered cAMP and MAPK 1,2 microdomains in cells of differing shapes. Since many diseases arise from malfunction of cell signaling pathways, understanding the role of cell shape in control of intracellular signaling will shed light on the origins of cancer, heart failure and kidney disease. These studies will provide new knowledge that will contribute to the process of putting image based diagnosis on firm biological principles. Thus, we anticipate the potential significance of the project will lie in its contributions to both the basic field of systems biology and the medical discipline of pathology.